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Zhang 2022 Nat Metab

From Bioblast
Publications in the MiPMap
Zhang CS, Li M, Wang Y, Li X, Zong Y, Long S, Zhang M, Feng JW, Wei X, Liu YH, Zhang B, Wu J, Zhang C, Lian W, Ma T, Tian X, Qu Q, Yu Y, Xiong J, Liu DT, Wu Z, Zhu M, Xie C, Wu Y, Xu Z, Yang C, Chen J, Huang G, He Q, Huang X, Zhang L, Sun X, Liu Q, Ghafoor A, Gui F, Zheng K, Wang W, Wang ZC, Yu Y, Zhao Q, Lin SY, Wang ZX, Piao HL, Deng X, Lin SC (2022) The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK.

ยป Nat Metab 4:1369-401. PMID: 36358567 Open Access

Zhang Chen-Song, Li Mengqi, Wang Yu, Li Xiaoyang, Zong Yue, Long Shating, Zhang Mingliang, Feng Jin-Wei, Wei Xiaoyan, Liu Yan-Hui, Zhang Baoding, Wu Jianfeng, Zhang Cixiong, Lian Wenhua, Ma Teng, Tian Xiao, Qu Qi, Yu Yaxin, Xiong Jinye, Liu Dong-Tai, Wu Zhenhua, Zhu Mingxia, Xie Changchuan, Wu Yaying, Xu Zheni, Yang Chunyan, Chen Junjie, Huang Guohong, He Qingxia, Huang Xi, Zhang Lei, Sun Xiufeng, Liu Qingfeng, Ghafoor Abdul, Gui Fu, Zheng Kaili, Wang Wen, Wang Zhi-Chao, Yu Yong, Zhao Qingliang, Lin Shu-Yong, Wang Zhi-Xin, Piao Hai-Long, Deng Xianming, Lin Sheng-Cai (2022) Nat Metab

Abstract: The activity of 5'-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.

โ€ข Bioblast editor: Plangger M โ€ข O2k-Network Lab: CN Xiamen Lin SC

Labels: MiParea: Respiration, Pharmacology;toxicology 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

Coupling state: LEAK, OXPHOS  Pathway: N, S, CIV, ROX  HRR: Oxygraph-2k